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Query: UNIPROT:P06889 (Mol)
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1. Coexisting with oxytocin or vasopressin in the cell bodies and nerve terminals of the hypothalamic-neurohypophysial system are smaller amounts of other peptides. For a number of these "copeptides" there is strong evidence of corelease with the major magnocellular hormones. Guided by the location of their specific receptors we have studied the effects of three copeptides, dynorphin, cholecystokinin (CCK), and corticotropin releasing hormone (CRH), on the secretion of oxytocin and vasopressin from isolated rat neural lobe or neurointermediate lobe preparations in vitro. 2. Dynorphin is coreleased with vasopressin from neural lobe nerve terminals and acts on neural lobe kappa-opiate receptors to inhibit the electrically stimulated secretion of oxytocin. Naloxone augments oxytocin release from the neural lobe in a manner directly proportional to the amount of vasopressin (and presumably dynorphin) released. 3. Cholecystokinin, coreleased with oxytocin by neural lobe terminals, has been shown to have high-affinity receptors located in the NL and to stimulate secretion of both oxytocin and vasopressin. CCK's secretagogue effect was independent of electrical stimulation and extracellular Ca2+ and was blocked by an inhibitor of protein kinase C. 4. CRH, coreleased with OT from the neural lobe, has receptors in the intermediate lobe of the pituitary, but not in the neural lobe itself. CRH stimulates the secretion of oxytocin and vasopressin from combined neurointermediate lobes but not from isolated neural lobes. Intermediate lobe peptides, alpha and gamma melanocyte stimulating hormone, induced secretion of oxytocin and vasopressin from isolated neural lobes. Their effect was, like that of CCK, independent of electrical stimulation and extracellular Ca2+ and blocked by an inhibitor of protein kinase C. 5. Among the CRH-producing parvocellular neurons of the paraventricular nucleus, in the normal rat, approximately half also produce and store vasopressin. After removal of glucocorticoid influence by adrenalectomy, virtually all of the CRH neurons contain vasopressin. 6. The two subtypes of CRH neurosecretory cells found in the normal rat possess different topographical distributions in the paraventricular nucleus, suggesting the possibility of differential innervation. Stress selectively activates the vasopressin containing subpopulation of CRH neurons, indicating that there are separate channels of regulatory input controlling the two components of the parvocellular CRH neurosecretory system.
Cell Mol Neurobiol 1989 Dec
PMID:Coexisting peptides in hypothalamic neuroendocrine systems: some functional implications. 257 30

Continuing our theoretical studies of the oxytocin and vasopressin analogues, we have analysed the molecular electrostatic potential (MEP) and the norm of the molecular electrostatic field (MEF) of [1-beta-mercaptopropionic acid]-arginine-vasopressin ([ Mpa1]-AVP), [1-(beta-mercapto-beta,beta-cyclopentamethylene)propionic acid]-arginine-vasopressin ([Cpp']-AVP), and [1-thiosalicylic acid]-arginine-vasopressin ([Ths']-AVP) whose low-energy conformations were calculated in our previous work. These compounds are known from experiment to exhibit different biological activity. The scalar fields mentioned determine the energy of interaction with either charged (MEP) or polar (MEF) species, the energy being in the second case either optimal or Boltzmann-averaged over all the possible orientations of the dipole moment versus the electrostatic field. The electrostatic interactions slowly vanish with distance and can therefore be considered to be the factor determining the molecular shape at greater distances, which can help in both predicting the interactions with the receptor at the stage of remote recognition and in finding the preferred directions of solvation by a polar solvent. In the analysis of the fields three techniques have been used: (i) the construction of maps in certain planes; (ii) the construction of maps on spheres centered in the charge center of the molecule under study and of poles chosen according to the main axes of the quadrupole moment; and (iii) the construction of surfaces corresponding to a given value of potential. The results obtained show that the shapes of both MEP and MEF are similar in the case of [Mpa1]-AVP and [Cpp1]-AVP (biologically active), while some differences emerge when comparing these compounds with [Ths1]-AVP (inactive). It has also been found that both MEP and MEF depend even more strongly on conformation.
J Comput Aided Mol Des 1989 Sep
PMID:Theoretical studies of the mechanism of the action of the neurohypophyseal hormones. I. Molecular electrostatic potential (MEP) and molecular electrostatic field (MEF) maps of some vasopressin analogues. 258 2

Vasopressin mRNA in the suprachiasmatic nucleus (SCN) of the rat brain exhibits diurnal variation in poly(A) tail length; a single species of mRNA identical in size to that in other hypothalamic nuclei is expressed in the light phase of the daily cycle whereas a second, smaller species is expressed in the dark phase. We have investigated the neuroendocrine factors which may regulate this rhythm by comparing vasopressin mRNA size with Northern analysis of RNA extracted from SCN tissue taken at 09.00 h (light phase) and 21.00 h (dark phase). The consistent rhythmic variation observed in normal male rats was not modified in either adrenalectomized or castrated animals or in ovariectomized female rats. The rhythm was also not disrupted following treatment with the serotonin-depleting agent parachlorophenylalanine, or following treatment with either melatonin or the benzodiazepine, triazolam. We next investigated whether the daily pattern of expression was maintained in isolated SCN. Microdissected blocks containing the paired SCN were explanted into culture at various times of the day for a period of 4 h. Vasopressin mRNA extracted from light phase cultures (11.00-15.00 h) exhibited no size change from control SCN mRNA taken at either 11.00 h or 15.00 h. In contrast, mRNA from cultures maintained over the period 16.00-20.00 h (lights off: 18.00 h) exhibited a marked size difference from 16.00 h controls, being similar to the smaller species observed in 20.00 h controls. Similarly, vasopressin mRNA from cultures maintained over the period 05.00-09.00 h (lights on 06.00 h) was similar in size to 09.00 h controls and contrasted to the pattern of expression observed in 05.00 h controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1989 Dec
PMID:Diurnal rhythm of vasopressin mRNA species in the rat suprachiasmatic nucleus: independence of neuroendocrine modulation and maintenance in explant culture. 259 78

Carboxypeptidase H (CPH) is a peptide-processing enzyme thought to be involved in the synthesis of many neuropeptides, including vasopressin (VP) and oxytocin (OT). In this study, employing in situ hybridization histochemistry, we have shown that CPH mRNA is abundantly expressed in the magnocellular paraventricular and supraoptic nuclei of the hypothalamus, the primary sites of OT and VP synthesis. Since this enzyme is copackaged in secretory vesicles and hence coreleased with the neurohypophysial hormones, enzyme stores are depleted in parallel with the peptide hormones during states of hypersecretion. Chronic osmotic stimulation, such as occurs in long-term salt-loading or in diabetes insipidus in the Brattleboro rat, causes depletion of neurohypophysial hormone stores and is accompanied by increased rates of neurohypophysial hormone transcription and translation. This study has shown that the expression of CPH mRNA is also significantly increased in oxytocin and vasopressin producing magnocellular neurons during chronic osmotic stimulation of the hypothalamic-neurohypophysial system. CPH mRNA levels in other peptidergic areas of the brain are not significantly changed by osmotic stimulation. These findings illustrate a coordinate regulation of the transcription of peptide hormones and an enzyme required for the hormones' posttranslational processing.
Mol Endocrinol 1989 Dec
PMID:Regulation of carboxypeptidase H gene expression in magnocellular neurons: response to osmotic stimulation. 262 43

The self-assembly properties of the arginine 8-vasopressin/bovine neurophysin II (AVP/BNPII) biosynthetic precursor were studied using glycopeptide-deleted and sequence-redesigned semisynthetic derivatives. Semisynthetic precursors were prepared by chemically coupling synthetic vasopressinyl sequence domains and native protein-derived neurophysin II domain. Measurement of precursor-protein association by the extent of affinity chromatographic retardation on agarose-immobilized BNPII verified that the semisynthetic precursor with native AVP sequence has an enhanced self-association propensity similar to that predicted for native precursor. Here, the stabilizing contacts between hormone and neurophysin domains, mainly the positively charged protonated alpha-amino group and tyrosyl 2 side chain of the hormone, are retained. Semisynthetic precursor variants in which the hormone domain is sequence-simplified by introducing alanyl residues in positions not considered important for neurophysin recognition show non-reduced association to BNPII. In contrast, removal of one of the main contact elements between hormone and neurophysin by acetylation of the hormone alpha-amino group abolishes potentiation of precursor self-association. The results show that the presence of the C-terminal glycopeptide sequence domain of native vasopressin precursor is not required to promote self-assembly of the precursor. The data verify the view proposed for the oxytocinyl precursor that intramolecular domain interaction is the triggering event which promotes the increase in affinity of precursor self-association (intermolecular self-recognition). The data also define some of the intramolecular self-recognition elements in the folded precursor required for the high affinity intermolecular self-recognition.
J Mol Recognit 1989 Apr
PMID:Sequence simplification and the intra- and intermolecular self-recognition properties of vasopressin/neurophysin biosynthetic precursor. 263 63

We have previously reported that the potent tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) and a factor from fetal calf serum (FCS) markedly enhance the transformation of mouse C3H 10T1/2 and Rat 6 fibroblasts, when added to cultures following transfection with plasmid pT24 DNA that contains an activated c-Ha-ras oncogene. In the present study, we examined possible enhancing or inhibiting effects of various chemicals on the transformation of Rat 6 fibroblasts by T24 DNA when tested in the presence of calf serum, calf serum plus TPA or FCS. We found that, like TPA, the chemicals mezerein, 1-oleoyl-2-acetylglycerol, and phospholipase C increased the yield of T24-induced foci, thus further implicating protein kinase C as a critical constituent in this process. Low concentrations (10(-6)-10(-7)M) of retinoic acid (both trans and 13-cis) also stimulated cell transformation. Several compounds inhibited T24-induced transformation. These included nontoxic concentrations of the calcium ionophore A23187, indomethacin, and epsilon-amino-n-caproic acid. Compounds that failed to exert a significant reproducible effect included vasopressin, vitamin D3, selenium, antipain, Bowman-Birk inhibitor, vitamin B12, epidermal growth factor, platelet-derived growth factor, insulin, and transferrin. These findings suggest that this simple in vitro system might be useful for detecting enhancers and inhibitors of ras oncogene-induced cell transformation and also elucidating their mechanisms of action.
Mol Carcinog 1989
PMID:Effects of various chemical agents on the transformation of rat fibroblasts by an activated c-Ha-ras oncogene. 266 19

The backbone conformations of the cyclic moieties of 1-[beta-mercaptopropionic acid]-oxytocin [( Mpa1]-OT), [1-beta-mercaptopropionic acid]-arginine-vasopressin [( Mpa1]-AVP), [1-(beta'-mercapto-beta,beta-cyclopentamethylene)propionic acid]-arginine-vasopressin [( Cpp1]-AVP), and [1-thiosalicylic acid]-arginine-vasopressin [( Ths1]-AVP) have been analyzed by means of molecular mechanics. In these calculations, the side chains were simulated by pseudoatoms. For the three last compounds, the calculations were also performed on the whole molecules, in order to shed light on the differences in their biological activity. Their starting conformations were obtained by attaching the acyclic tail and side chains to the lowest energy conformations of the cyclic parts. In the case of [Ths1]-AVP, however, other starting conformations were also examined, which were obtained by attaching the planar benzene ring to the lowest energy conformations of [Mpa1]-AVP. In the calculations, all the degrees of freedom were relaxed and Weiner's force field was used, the parameters required for the benzene parts of [Ths1]-AVP being determined from the experimental data available, as well as from the results of molecular dynamics calculations on the model compounds. The lowest energy conformations of [Mpa1]-AVP and [Cpp1]-AVP are similar, while [Ths1]-AVP differs from them near the disulphide region, due to the presence of a planar benzene ring. Interactions involving the charged guanidine group of arginine make, in each case, an important contribution to the conformational energy. A model description of the shapes of the oxytocin and vasopressin ring has been proposed, which is based on the cyclohexane geometry. This description is in good correlation with the energetics of the conformations corresponding to different shapes.
J Comput Aided Mol Des 1989 Jan
PMID:Molecular mechanics calculations on deaminooxytocin and on deamino-arginine-vasopressin and its analogues. 271 90

1. We have studied the localization, kinetics, and regulation of receptors for the circulating form of the atrial natriuretic peptide (ANP; 99-126) in the rat brain. 2. Quantitative autoradiographic techniques and a 125I-labeled ligand, 125I-ANP (99-126), were employed. After in vitro autoradiography, quantification was achieved by computerized microdensitometry followed by comparison with 125I-standards. 3. ANP receptors were discretely localized in the rat brain, with the highest concentrations in circumventricular organs, the choroid plexus, and selected hypothalamic nuclei involved in the production of the antidiuretic hormone vasopressin and in blood-pressure control. 4. Spontaneously (genetic) hypertensive rats showed much lower numbers of ANP receptors than normotensive controls in the subfornical organ, the area postrema, the nucleus of the solitary tract, and the choroid plexus. These changes are in contrast to those observed for receptors of angiotensin II, another circulating peptide with actions opposite to those of ANP. 5. Under conditions of acute dehydration after water deprivation, as well as under conditions of chronic dehydration such as those present in homozygous Brattleboro rats, there was an up-regulation of ANP receptors in the subfornical organ. 6. Our results indicate that in the brain, circumventricular organs contain ANP receptors which could respond to variations in the concentration of circulating ANP. In addition, brain areas inside the blood-brain barrier contain ANP receptors probably related to the endogenous, central ANP system. 7. The localization of ANP receptors and the alterations in their regulation present in genetically hypertensive rats and after dehydration indicate that brain ANP receptors are probably related to fluid regulation, including the secretion of vasopressin, and to cardiovascular function. ANP and angiotensin II could act as mutual antagonists in the brain as they do in the periphery. 8. ANP receptors in the choroid plexus may be related to the formation of cerebrospinal fluid.
Cell Mol Neurobiol 1987 Jun
PMID:Regulation of atrial natriuretic peptide receptors in the rat brain. 282 May 78

This study reports the presence in AtT-20 corticotrophs of high affinity-low capacity receptors for arginine-vasopressin (AVP), whose binding capacity was considerably enhanced by the divalent metal ion nickel. These binding sites, when analyzed in the presence of nickel, showed high affinity for AVP, vasotocin and oxytocin, but recognized to a lesser extent the V2-agonist 1-deamino-AVP, as well as V1-antagonists. Surprisingly, AVP failed to alter secretion of proopiomelanocortin (POMC)-derived peptides from the cells or corticotropin-releasing factor (CRF)-induced cAMP synthesis, as reported in normal corticotrophs. Exposure of cells to CRF elicited an increase in mRNAPOMC levels, while, in contrast, AVP was without significant effect. It thus appears that in AtT-20 tumor cells, the AVP receptors are not coupled to either the biochemical or biological cellular response.
Mol Cell Endocrinol 1987 Oct
PMID:Evidence that AVP receptors in AtT-20 corticotrophs are not coupled to secretion of POMC-derived peptides. 282 11

We examined the effects of oxytocin on renal tubular epithelial LLC-PK1 cells. In cells loaded with Fura 2, we found that 1 microM oxytocin induced a rapid increase in cytosolic free [Ca2+]i from 120 nM to 250 nM within 12 sec. [Ca2+]i then decreased and leveled at 148 nM. Calcium was mobilized from intra- and extra-cellular sources. Oxytocin-induced calcium mobilization was dose dependent (EC50 between 5 and 30 nM). Oxytocin also stimulated calcium efflux which was blocked by the selective oxytocin antagonist KB-5-21. Calcium mobilization was a likely consequence of enhanced phosphatidylinositol turnover, because oxytocin rapidly increased the formation of inositol phosphates including Ins1,4,5P3. Calcium transients were induced by oxytocin and the oxytocin selective analog AM-2-40 and blocked by the oxytocin-selective antagonist KB-5-21. Lysine vasopressin, the selective V2 agonist dDAVP, and the V1-selective agonist SK&F 105349 were at least 10- to 100-fold less potent than oxytocin and exhibited only partial agonist activity. Using peptide analogs, a poor correlation was found between antagonism of oxytocin-induced calcium transients of LLC-PK1 cells and pig kidney V2 and rat liver V1 receptor affinity. These data indicate that oxytocin-induced calcium transients in LLC-PK1 cells were not mediated by V1 or V2 vasopressin receptors, but by oxytocin receptors. However, the poor correlation between antagonism at the LLC-PK1 receptors and the rat uterus oxytocin receptors suggests marked differences in antagonist recognition. We have also identified specific, saturable, high affinity oxytocin-binding sites of low density on intact LLC-PK1 cells (KD = 1.9 nM; Bmax = 3.2 fmol/10(6) cells). The relative analog affinities for these binding sites correlated well with their effects on oxytocin-induced calcium transients. We conclude that in LLC-PK1 cells, oxytocin stimulates a transient rise in cytosolic free [Ca2+]i and the formation of inositol phosphates, including Ins1,4,5P3. The effects on [Ca2+]i probably are not mediated by V1 and V2 vasopressin receptors, but by putative oxytocin receptors.
Mol Pharmacol 1988 Feb
PMID:Oxytocin induces a transient increase in cytosolic free [Ca2+] in renal tubular epithelial cells: evidence for oxytocin receptors on LLC-PK1 cells. 282 15


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